Reconstituting human primitive streak formation through extra-embryonic cell coordination

Gastrulation is the fundamental stage of human development, governed by the faithful interaction between embryonic and extra-embryonic tissues. Despite its significance, the role of extra-embryonic lineages in directing embryonic diversification and organization remains elusive. Here, we developed a defined co-culture system where embryonic stem cells (ESCs) are cultured with various extra-embryonic cell types, mimicking in vivo amniotic ectoderm, trophoblast, and extra-embryonic mesoderm, and uncovered the previously unrecognized role of different extra-embryonic cells in regulating embryonic cells. Furthermore, leveraging the advantages of microengineering techniques, we spatially and molecularly reconstructed the interactions among distinct extra-embryonic and embryonic cells, demonstrating that the coordinated regulation of extra-embryonic cells alone can recapitulate the human primitive streak (PS) formation, while also exhibiting extended developmental potential. This advancement may allow for experimental exploration and manipulation of previously inaccessible stages of human early gastrulation, providing an opportunity to glimpse the onset of this crucial developmental process.